This paper provides the state-of-the-art in hydrologic modeling regarding its capability of predicting the effects of climate and land use change on the hydrological cycle. In conclusion, the research challenges are pinpointed, which the community should address as to be able to observe and model, at a regional-scale, the coupled climate-water cycle in response to the human induced changes in climate and land use. The findings presented herein are a compilation resulting from an extensive literature review and the personal expertise of the authors. Given the focus on hydrologic modeling, many other aspects such as the best practices of integrated water resources management, cross-boundary water governance, the establishment of institutional frameworks, empowerment of local communities to participate effectively in water management and policy making, among many other very relevant aspects, were intentionally not considered as not to dilute the focus of the paper.